Related papers: Assessing models of force-dependent unbinding rate…
Receptor-ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, detailed information of the full…
We here report on non-equilibrium targeted Molecular Dynamics simulations as tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray…
Analysis of bond rupture data from single-molecule force spectroscopy experiments commonly relies on the strong assumption that the bond dissociation process is irreversible. However, with increased spatiotemporal resolution of instruments…
A key factor influencing a drug's efficacy is its residence time in the binding pocket of the host protein. Using atomistic computer simulation to predict this residence time and the associated dissociation process is a desirable but…
Molecular motors walk along filaments until they detach stochastically with a force-dependent unbinding rate. Here, we show that this unbinding rate can be obtained from the analysis of experimental data of molecular motors moving in…
Prediction of protein-ligand binding affinity is a major goal in drug discovery. Generally, free energy gap is calculated between two states (e.g., ligand binding and unbinding). The energy gap implicitly includes the effects of changes in…
We incorporate hydrodynamic interactions in a structure-based model of ubiquitin and demonstrate that the hydrodynamic coupling may reduce the peak force when stretching the protein at constant speed, especially at larger speeds.…
Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and…
Protein-ligand (un)binding simulations are a recent focus of biased molecular dynamics simulations. Such binding and unbinding can occur via different pathways in and out of a binding site. We here present a theoretical framework how to…
Lifetimes of bound states of protein complexes or biomolecule folded states typically decrease when subject to mechanical force. However, a plethora of biological systems exhibit the counter-intuitive phenomenon of catch bonding, where…
Mechanical forces acting on cell adhesion receptor proteins regulate a range of cellular functions by formation and rupture of non-covalent interactions with ligands. Typically, force decreases the lifetimes of intact complexes…
Recently experiments showed that some biological noncovalent bonds increase their lifetimes when they are stretched by an external force, and their lifetimes will decrease when the force increases further. Several specific quantitative…
We probe the dynamic strength of multiple biotin-streptavidin adhesion bonds under linear loading using the biomembrane force probe setup for dynamic force spectroscopy. Measured rupture force histograms are compared to results from a…
Mechanically induced protein unfolding in the force-clamp apparatus is shown, in a coarse-grained model of ubiquitin, to have lognormal statistics above a treshold force and exponential below it. Correspondingly, the mean unfolding time is…
Myosin motors are fundamental biological actuators, powering diverse mechanical tasks in eukaryotic cells via ATP hydrolysis. Recent work revealed that myosin's velocity-dependent detachment rate can bridge actomyosin dynamics to macroscale…
We present two methods to reveal protein-ligand unbinding mechanisms in biased unbinding simulations by clustering trajectories into ensembles representing unbinding paths. The first approach is based on a contact principal component…
We examined theory for force-induced unbinding on a two-dimensional free energy surface where the internal dynamics of biomolecules is coupled with the rupture process under constant tension f. We show that only if the transition state…
Ligand-receptor binding and unbinding are fundamental biomolecular processes and particularly essential to drug efficacy. Environmental water fluctuations, however, impact the corresponding thermodynamics and kinetics and thereby challenge…
A quantitative understanding of how cells interact with their extracellular matrix via molecular bonds is fundamental for many important processes in cell biology and engineering. In these interactions, the deformability of cells and matrix…
Force-clamp spectroscopy reveals the unfolding and disulfide bond rupture times of single protein molecules as a function of the stretching force, point mutations and solvent conditions. The statistics of these times reveal whether the…